Project Abstract A growing body of evidence suggests that obesity is associated with alterations in brain structure and cognitive impairment. Mid-life obesity is a risk factor for Alzheimer's disease and vascular dementia. The mechanisms underlying obesity related decline in cognitive function are not fully understood. The long-term goal of our research is to identify how obesity, insulin resistance (IR), and their treatment impact brain structure and function. We propose that IR and obesity related inflammation are two modifiable factors that affect neuronal integrity and lead to cognitive dysfunction. In this proposal, we will test two hypotheses: 1) among obese patients planning to undergo bariatric surgery (specifically vertical sleeve gastrectomy), baseline IR and systemic and brain markers of inflammation will inversely correlate with performance on cognitive testing and correlate with abnormalities in brain structure and 2) following bariatric surgery subjects who experience the greatest reduction in IR and obesity related inflammation will have the greatest improvement in cognitive function and brain structure. To address our hypotheses, we will use a comprehensive battery of tests to evaluate cognition and state of the art magnetic resonance imaging (MRI) techniques to assess brain structure and neurochemistry before and six months after bariatric surgery. Aim 1: To examine the associations of obesity, IR and inflammation with neural integrity, white matter microstructure and cognitive function. Specific Aim 1: To measure IR, blood inflammatory markers, comprehensive regional brain neurochemical profile in the hippocampus and in the anterior cingulate cortex (ACC) using proton magnetic resonance spectroscopy (1H-MRS) and fractional anisotropy (FA) in white matter tracts using diffusion tensor imaging (DTI), and to perform neurocognitive testing in obese subjects planning to undergo bariatric surgery and in age, sex, and education matched normal weight controls. Aim 2: To determine the effects of improvements in IR and inflammation and weight loss on neural integrity, white matter microstructure and cognitive function. Specific Aim 2: To repeat the measures of IR, blood inflammatory markers, hippocampal and ACC neurochemical profiles, and FA in white matter tracts, and to perform neurocognitive testing in obese subjects recruited for aim 1 six months after undergoing bariatric surgery